FTO Demethylates Cyclin D1 mRNA and Controls Cell-Cycle Progression
Mayumi Hirayama1, Fan-Yan Wei2, Takeshi Chujo3
1Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto-Shi, Kumamoto 860-8556, Japan; Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto-Shi, Kumamoto 860-8556, Japan.
Cell Reports
|April 9, 2020
Summary
Fat mass and obesity-associated (FTO) protein regulates cell proliferation by demethylating m6A modification of cyclin D1 mRNA. FTO depletion impairs cell cycle G1 progression by increasing cyclin D1 mRNA degradation.
Area of Science:
- Molecular Biology
- Epigenetics
- Cell Biology
Background:
- N6-Methyladenosine (m6A) is a crucial mRNA modification regulating gene expression and fundamental biological processes.
- Cell proliferation is tightly controlled, with disruptions implicated in diseases like cancer.
- Cyclin D1 is a key regulator of the G1 phase of the cell cycle, controlling cell division.
Purpose of the Study:
- To investigate the role of the fat mass and obesity-associated (FTO) protein in regulating m6A modification of cyclin D1 mRNA.
- To elucidate the impact of FTO-mediated demethylation on cyclin D1 mRNA stability and cell proliferation.
- To understand the cell-cycle-dependent regulation of m6A modification and FTO activity.
Main Methods:
- Studied the interaction between FTO and cyclin D1 mRNA.
- Utilized in vitro and in vivo models to assess the effects of FTO depletion on cell proliferation and G1 phase progression.
- Analyzed m6A modification levels of cyclin D1 mRNA throughout the cell cycle.
- Investigated the subcellular localization of FTO and its regulation by phosphorylation.
Main Results:
- FTO directly demethylates m6A modification of cyclin D1 mRNA.
- FTO depletion leads to increased m6A modification of cyclin D1, accelerating its mRNA degradation and impairing G1 progression.
- Cyclin D1 m6A modification exhibits cell-cycle-dependent oscillations, with lower levels in G1 phase.
- FTO nuclear translocation during G1 phase is linked to low m6A levels and is regulated by casein kinase II-mediated phosphorylation.
Conclusions:
- FTO plays a critical role in regulating cyclin D1 mRNA stability through m6A demethylation.
- This mechanism adds a new layer of complexity to cell-cycle regulation.
- Understanding FTO's role in m6A modification offers potential therapeutic targets for diseases involving cell proliferation.
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